Margaret’s Story

(The story outlined below is authored by ‘Margaret’. Since this was first written there have been a number of developments and an update to ‘Margaret’s Story’ will follow – DH).

Our son went to his GP with poor sleep because of worries at work. His doctor said he was depressed and put him on a combination of Cipramil (SSRI antidepressant) and Temazepam (a sleeping pill). A week later he took his own life. We now question both the diagnosis and the combination of medications – a mixture of uppers and downers.

Many of those who take their lives have recently attended the doctor. It must be important to see if there are any links between the use of medication and death. In the time since his death we have had a steady correspondence with the Department of Health and MHRA in an attempt to clarify how anyone can come to be placed at risk of suicide from their treatment. We would consider ourselves to be well-informed but we had no idea that mind-altering drugs are prescribed so widely with negligible safeguards.

The system… is deemed to be adequate

Early on we discovered enough about Cipramil and other SSRIs to give us cause for concern. This has been the driving force behind our enquiries since. We have written to a succession of Ministers of Health and received replies from the offices of Andy Burnham and Mike O’Brien saying in effect that the current system, with regard to maintaining the best practice in the use of SSRI antidepressants, is regularly reviewed and is deemed to be adequate.

We were directed to the regulator, the MHRA, and this led to a back and forth between the MHRA and Department of Health and ourselves. We have been sent an abundance of correspondence that invariably buries whatever issue we address in a welter of references to complying with the European Union and the CSM Working Group, along with directions to seek further information at the NICE website or MHRA’s own website etc.

This is not acceptable for someone seeking advice in plain English to find that it isn’t readily available. There is no apparent will to put information about SSRIs in the public domain. It has to be sought out and cannot easily be found. Updated information, it seems, gets posted to locations not easily accessible to the public at large.

The unalienable right for all patients and their carers to know about risks

Virtually every time I have corresponded with the Department of Health or MHRA I have referred to the BNF guidance that:

“the use of antidepressants has been linked with suicidal thoughts and behaviour. Where necessary patients should be monitored for suicidal behaviour, self-harm or hostility, particularly at the beginning of treatment or if the dose is changed”.

This two-sentence warning, and what I feel is the unalienable right for all patients and their carers to know about risks, has been at the heart of my enquiries. But it has never been addressed. The MHRA drew my attention to the NICE advice:

“Depression and anxiety commonly co-exist, and insomnia is a core symptom of depression. Whereas antidepressants usually take two to four weeks to take effect, benzodiazepines are effective anxiolytic and hypnotic drugs with an immediate onset of action. Therefore benzodiazepines could be expected to produce early improvement in some symptoms of depression, although they do not have an antidepressant effect.”

This advice ties together depression, anxiety and insomnia. It seems to direct the physician towards the use of antidepressants as a cure-all. The implication is that a benzodiazepine could help the patient initially until the antidepressant reaches a “therapeutic” level. But NICE does not recommend long term augmentation of antidepressants with benzodiazepines. As ever, the message is confused.

If the drugs take two weeks and more to work for good, then they take the same time to harm

The NICE advice, it seems to me, is being used as a fig-leaf to cover the failure to address the more dangerous period of early uptake or dosage amendment (which the MHRA choose to interpret as ‘at the point of increase’, not the dreadful time of withdrawal experienced by those with long-term repeat prescriptions who wish to stop, or those who do not sustain regular dosage). Significantly, NICE does not address the question of whether there are critical points in usage. It seems that so many interpret their advice as meaning that if the drugs take two weeks or more to work for good, then they take the same time to harm.

When, on the day he died, our son presented at an A&E unit, he saw a doctor who was not a psychiatrist. He was informed of our son’s medication details and has since stated that, although he was aware of the suicide risk of Cipramil he did not alert our son to this. Part of the hospital’s explanation for this lapse was adherence to the “two weeks to improve therefore two weeks to deteriorate” mantra embodied in the NICE advice.

Where this originally comes from is still a mystery. Our son was left without hope or insight that would have told him he was in a temporary state of crisis that could be addressed with proper medical assistance. The NICE advice is at odds with the BNF warning, and so conflicting messages are being sent to those seeking guidance.

All leaflets should contain a suicide risk warning

Much of our correspondence has centred on the failure of the PIL – the patient information leaflet – as a means of communicating risk. The MHRA assured me that all leaflets should contain a suicide risk warning, combined with the advice to appoint a relative or friend to read the leaflet and monitor the patient. I found that the Cipramil leaflet in my possession did not have the combined message. The suicide risk was mentioned, though not at all well highlighted. The advice to appoint a monitor was not there.

I received a grudging reply that steps were “being taken by the MHRA to ensure the PIL for this particular Citalopram [Cipramil] product is updated to include the full warning”. No acceptance that the current system fails and no wish to revise existing practices. I had wrongfully assumed that all PILs had to replicate a master produced by the MHRA for each drug – not so. There is no apparent will to raise the level of the suicide warning in the PILs for antidepressants.

When I asked why the two sentence advice from the BNF could not be in the public domain I was told that “it is not feasible to have a public campaign to inform all patients about the side effects associated with all of the medicines on the UK market”. I replied that SSRIs could be classed as a group and are used by so many patients that it was well worth circulating vital information about potential risks. I received no reply to this comment.

According to the Office of National Statistics, 39 million prescriptions were issued for antidepressants in 2009. Even factoring in a calculation for repeat prescriptions, the number of patients using antidepressants runs into millions. This establishes them as a considerable proportion of patients who need to be as well-informed as possible, given the suicide risk their medication can give rise to.

Who decides who lives and who dies?

I wrote to Anne Milton, Under Secretary of State for Public Health, expressing my concerns and dissatisfaction with the response of the MHRA and also copied the current Minister for Health, Andrew Lansley, into a letter I wrote to the MHRA. I was then switched to the Department of Health and I was told that the

“Department believes a balance has to be reached between raising awareness and deterring people from taking antidepressants which can and do prove to be very effective treatments …..”

This “effective treatment”, if it exists, is being achieved at the cost of the lives of a vulnerable minority, no reference to this of course. Who decides who lives and who dies – shouldn’t we know about these risks, especially when knowing about them means that more might live?

The Department believes that my concerns over public awareness have been well covered in the press and the scientific media. Really? The Department has deemed that

“the PIL is a patient aid and does not replace the discussion between the prescriber and the patient. It is good clinical practice to discuss the potential risks as well as the benefits of a treatment, prior to issuing a prescription”.

Plainly, nobody has told the prescribers this. It appears to me that ill-informed and pressurized GPs are just as much victims of the current failing system as the patients. The emphasis on targets has led to foreshortened consultation time and quick-fix prescription of medication.

In a bizarre twist I was directed towards the General Medical Council

Then in a bizarre twist I was directed towards the General Medical Council (GMC) by Department staff as “….the training and development of medical professionals is the role of the GMC.” The Department says it does not investigate the conduct of doctors but

“the GMC seeks to promote high standards and ensure that medical education and training reflects the needs of patients, the service, students and trainees. Your concerns about the lack of knowledge regarding antidepressants should also be directed to the GMC”.

I approached the GMC. They did not respond to my query as to whether or not the seemingly counteractive combination of antidepressant and sleeping medication is deemed to be accepted practice. They have chosen to deal with this as a fitness to practise issue and gave me a deadline by which time they wished to receive the names of the GP and A & E doctor involved in our son’s case. Otherwise they would assume that I wish no further investigation. I have refused to comply, as I don’t see the doctors as being to blame.

As a result the GMC now consider that they are not the best agency to deal with my concerns. I have been told that they “are not a part of the NHS or Department of Health and have no powers to affect generalized policies. Concerns about the system, that is NHS procedures or the way that medics are trained, does not generally fall within our remit.”

This seems to be a complete contradiction to the promise of the Department of Health that training and development of medics is in the remit of the GMC – they are talking totally at cross purposes.

The Department will be unable to enter into further correspondence with you on this matter

The GMC directed me to the Parliamentary and Health Services Ombudsman, our local MP and, ironically, back to the MHRA. Exasperating to say the least. The Department of Health meanwhile now tells me that

“unless there are any subsequent developments surrounding the labelling of UK prescription medications, the Department will be unable to enter into further correspondence with you on this matter.”

The authorities refuse to listen or respond. At a time when the situation is fluid and changing as more information emerges about adverse drug reactions, the authorities are set in concrete or stagnant. If you are not satisfied with their reply, then it is your fault and you are not to bother them again. This institutional heedlessness parallels the stance of the pharmaceutical companies when a patient is not responding well to their drug – it must be down to the patient and not the drug.

The system is failing patients and doctors. Doctors are not trained to look out for or to deal with adverse drug reactions. Medication is not accompanied by adequate patient information and the doctor is not instructed to outline clearly the potential dangers to the patient. We can’t improve the system unless we recognize the inadequacies.

Out in the real world, precious lives are being lost to horrific avoidable deaths.

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Comments

Perhaps the MHRA are less enthusiastic about making a huge deal about the suicide risk because untreated depression is a far greater suicide risk than SSRIs, and there is ongoing debate about whether the American experience with the FDA black box warning increased suicide rates due to decreased SSRI uptake.

@Neil
“So the people that kill themselves due to these drugs are what? Disposible, acceptable loss…what are you saying, that they died for the greater good?”
Of course no one is disposable. But unfortunately, all drugs have side effects. People should be warned about possible side effects, and if they weren’t it’s a horrific shame; but it’s the clinician’s fault, not the drugs. Nobody asked them to sacrifice themselves “for the greater good”, they died trying to cure themselves for their own good.

“And you know untreated depression is a far greater risk than SSRI’s how?”
Because the SSRI link is controversial and not reproduced in all studies or meta analysis, despite the impression you might get from reading this site, whereas the link between depression and suicide is eminently reproducible.

@Maria
“…depression is linked with suicidal thinking, the links with completed suicide are weak. …Those on psychiatric drugs however for both psychiatric and non-psychiatric disorders self harm and suicide at an alarming rate. ”

I’m afraid I’ll need some citations for those claims. The WHO have evidently not updated their pages on suicide or depression so it must be very recent indeed.

“People should be warned about possible side effects, and if they weren’t it’s a horrific shame; but it’s the clinician’s fault, not the drugs”

A horrific shame… So your saying its the clinicians fault then. You local GP has all the facts about every drug? Or maybe you think because its mentioned somewhere in the PIL in 4pt text using medical jargon its the patients fault. The risks were there for them to see as long as they have good internet skills and a few weeks to do the research. Its any ones fault but the companies or regulators?

And why do you think it is that most clinicians have next to no idea that these horrible side effects even exist. Even the ones that specialize in the field!

I am speaking from personal experience here so yeah you can trash my anecdote all you want, which of course is the way now of SBM isn’t it? We all live in a world were we cannot accept anything in our reality unless a couple of suspect RCT’s say its so. How the future will laugh at us.

Of the three GP’s, one Psychiatrist and one CPN I have talked to recently, all have said that there is NO WAY my wife’s adverse affects have anything to do with the drugs, despite them being listed on the PIL, despite the problems going away only after the drugs had been discontinued.

When my wife asked her GP to send a yellow card to MRHA, her GP ordered blood tests to explain away soem of the physical issues. He completely dismissed her drastic personality change and destruction of her family. When the blood test came back ok, he ordered more blood tests saying there where a few things he didn’t check for. I am going to be interested to see what he does when these test come back clear. Will he suggest its all in her head…that is were my money is.

Where exactly do these professionals get their information from? Drug reps maybe?

In a cruel twist of fate, 7years ago I was best man at the wedding of the man who went on to sell the very drug that nearly destroyed my family. When I told him about the adverse reactions we had experienced, he claimed it was the first even he had even heard of it.

“SSRI link is controversial and not reproduced in all studies or meta analysis, despite the impression you might get from reading this site”

SSRI’s are contorversal full stop, as are the studies and analysis, surely you know this. As for non medicated depression and suicide, … clean data on suicide from depressed patients who have NEVER been medicated. I read a little about that subject in Anatomy of an Epedmic but it was a while ago so I can’t quite remember what the data said exactly. But I would be really interested to see that. Really interested. NEVER medicated now, not just poeple not on medication at the time, otherwise I am not interested.

Jamie, everything is not ok with the current situation. Sites like this are hopefully a tiny step towards putting that right.

Surely Margaret’s son deserved to be told that the symptoms he was experiencing were a possible side-effect of the drug? Then again; what if the medical staff are not aware of this? There is a big possibility that if they were aware, then Margaret’s son would still be alive. I hold a different view; I cannot understand how doctors could not be aware that suicide ideation can accompany SSRI’S. Surely the doctors have Google? The side-effect ‘suicide ideation’ is also listed, at least with Cipramil, in the Doctor’s trainee manual.
I too have written to the Irish equivalent of the MHRA, the Irish Medicine’s Board (IMB) to raise my concerns about the serious lack of warnings in the PIL’s. They have done nothing to rectify this as yet, but this is hardly surprising as the IMB are 87% funded by the pharmaceutical Industry. I also made a complaint to the Medical Council of Ireland (MCIRL) about the care or lack of care that Shane received in the last 17 days of his life. The MCIRL said they did not have the SSRI expertise to deal with Shane’s case and would have to get an outside ‘independent’ report. I informed them that you did a detailed Report for Shane’s Inquest and insisted on E-mailing it to them. Anyway, they also got an ‘independent’ report from an Oxford University Professor, Philip J. Cowen, who happens to do an awful lot of work for Lundbeck (the makers of Citalopram). I did point this out to the MCIRL. The unsurprising result was that the MCIRL eventually decided there was no case to answer.

I then decided to write to the Irish Human Rights Commission (IHRC), as under the 1937 Constitution of Ireland, Shane had a fundamental ‘right to life’. After reviewing my correspondence with the IMB, MCIRL, Shane’s medical records, Citalopram PIL’s, Doctor’s statements and both reports, the IHRC decided to take some action…
In December 2011, the IHRC wrote to the Medical Council requesting that, inter alia, patients are informed of the potential side effect of suicide ideation with SSRI’s and for closer monitoring and ongoing supervision when SSRI’s are initially prescribed.
The IHRC suggested that consistency of care of persons presenting with symptoms of depression would be served by ensuring that the following matters are expressly required to be explored and addressed by the medical practitioner with their patient:
(i) Discussion of alternate therapies
(ii) Referrals for counselling/psychiatric review
(iii) Within medical practices seek to ensure the same doctor deals with the person at all stages if at all possible;
(iv) Oral explanation of risks/side-effects of SSRI’s in advance of prescription, together with relevant written information;
(v) Guidelines regarding prescribing SSRI’s from initial stage through ongoing treatment;
(vi) Level of monitoring and ongoing supervision required when SSRI’s are initially prescribed
(vii) Maintenance of adequate consultation notes; and
(viii) The necessity to obtain a full patient history before prescribing SSRI’s
It remains to be seen whether the IMC has acted upon this, somehow I doubt it.
Leonie

I remember meeting with the CEO of the MHRA, although it was a meeting to do with SSRi withdrawal, he told me he would write to the BNF to relay my concerns about the lack of advice given for tapering methods. That was a few years ago, it’s pretty much unchanged.

David Healy, the author of this blog, also met with them a year or so after. He presented them with a withdrawal protocol…

It still remains on the MHRA table collecting cobwebs.

Margret’s story is tragic, made even more so by the limp-wristed lickspittles at the MHRA who, once again have seen to be dragging their heels in the hope that a grieving parent will just ‘go away’.

Actually Jamie, more recent research by the World Health Organisation shows that while depression is linked with suicidal thinking, the links with completed suicide are weak. Around the world, governments estimate that up to half the population will suffer a depressive episode. An infinitesimal proportion of those people kill themselves. Those on psychiatric drugs however for both psychiatric and non-psychiatric disorders self harm and suicide at an alarming rate. The argument that untreated depression is a greater suicide risk than psychiatric drugs doesn’t therefore stack up.

No, Jamie, as Maria states, your argument doesn’t stack up. It wouldn’t stack up if SSRI’s were prescribed solely for severe depression, but when they’re dished out for complaints ranging from backache to PMS, then your argument becomes completely irrelevant.

The huge deal for the MHRA is that they are funded by drug companies who put profit before patient safety. How much funding have the drug companies or health authorities put into proper assessment of the SSRI risk once in general use? They will always wish to conclude that the problem must be the patient not the drug, it is in their shared interest to do so.
The MHRA has not put an effective system in place for recording the statistics for SSRI-linked suicide. Plainly they do not wish to see the results.

In an analysis of placebo controlled trials submitted to FDA on antidepressants used for anxiety indication Khan et al (2002), J of Affective Disorders 68, 183-190, report 11 suicides in 12,914 patients on antidepressant, versus 0 suicides in 3,875 patients taking placebo. The worst of the antidepressants was clomipramine which is a potent serotonin reuptake inhibitor.

But that difference is almost certainly not statistically significant. If the rates were exactly the same in placebo as for antidepressant, we would only expect to see 3 suicides in the placebo group. A difference of 3 rare events in 3875 people is not enormously different from chance!

From the paper:
“We conducted a series of Chi-square tests to assess statistically significant differences among anti-anxiety agents (both investigational and active comparators) treated patients compared to those treated with placebo for incidence of suicide and suicide attempts. The only statistically significant pattern was a higher risk for suicide attempts for those assigned to active comparators (alprazolam or clomipramine) in the anti-panic agent studies (X2=7.75, df=2, P=0.021). The available data do not allow us to evaluate risk for those assigned to alprazolam compared to those assigned to clomipramine.”
And if you look at the figures that risk (which may be due to the benzo comparator anyway) is coming from one (1) extra unsuccessful suicide attempt in the active comparator group. This paper does not seem supportive of the idea that antidepressants cause suicide attempts.

Jamie if you choose to read an increase in suicides that might have arisen by chance as not actually an increase you’re welcome to do so but its rather like regarding a gun as not loaded because some of the barrels are empty and if you take your chances you might be okay. If you can find me a regulator or company person who would join you in such a roulette, let me know.

I suggest you read back through all the entries on the blog. If you think company coding of withdrawal suicides as placebo suicides in breach of FDA regulations was probably just innocent (likely applies to some of the supposed placebo suicidal acts in this Khan paper) that’s your prerogative. If you think company monitors were wrong to say their SSRI had caused healthy volunteers to become agitated, apprehensive and have violent thoughts – again fine. If you think there’s nothing abnormal about healthy volunteers commiting suicide on serotonin reuptake inhibitors and companies were wrong to settle the cases – well no-one knows who you are and no-one expects you to be able to justify your position.

But I do expect regulators and companies to justify their position, and they haven’t. The next series of posts will cover this issue in greater detail.

It’s called statistical analysis, David, not Russian roulette. If you can’t show that your purported increase in suicide risk is actually a real increase and not simply due to the fact that a certain expected number of people in any group will commit suicide over a given period of time, there’s no reason to go after the drugs. Given that the Khan paper is about how anxiety is actually a bigger risk for suicide than had been thought, a 0% rate of suicides is probably down to the sample size not being big enough to reliably pick up rare events.

Maybe the drugs companies have fiddled the figures; that’s a separate argument, and I’ll read your posts about it. Presumably since you cited those figures from Khan et al. to me, though, you think they’re valid. On any level of academic rigour beyond “it looks like a real increase to me”, they don’t support a link between antidepressants and suicide. The part you should be interested re: bias in is the fact that there is an apparent increase in risk (note that it has been analysed properly, but may be due to a benzo) which only appears when the drug is used as a comparator, not as active treatment.

Most studies are pooled to make them look good. Add a few negative studies to ‘positive’ studies and voila you have the results you need.

You fail to recognise the long term issue as well. What happens to patients who have been on these types of drugs for a year or more?

That’s when Post-Marketing Surveillance is supposed to come in to play – but it doesn’t really.

Saying a drug causes x,y, or z isn’t enough. It should be investigated why it causes x, y or z.

If 3875 people ate food at a restaurant and three of them died as a result of food being served at that restaurant, would that be just ‘chance’?

We have a regulator logging yellow card reports but doing very little follow-up, we have an industry, who have made of 3,000 out of court settlements in the US on Seroxat withdrawal alone, almost 800 out of court settlements on Seroxat birth defects.

Withdrawal issues and birth defects were known very early on but they chose to suppress that information.

As patients we are entitled to informed consent, we should know all the facts and not just the ones cherry picked by pharma.

Have you ever tried to ask for withdrawal advice from any pharmaceutical company Jame? Try it and get back to me with their advice.

Jamie – what you’re offering is not statistical analysis – you’re using doubt is our product as a defense to suggest that a substantial increase is no increase. See the Psychotic Doubt post.

The Khan paper is extraordinary on a number of fronts. They say the common understanding in the field is anxiety poses no risk of suicide. This is consistent with the findings on placebo – zero suicides. If people in the UK committed suicide at the rate that patients on drugs with anxiety in the Khan study committed suicide there would be 62,000 suicides in the UK per year – a 10 fold higher rate than there is. They offer no basis for concluding that anxiety rather than the drugs pose a risk of suicide – I commonly show these figures and the Khan conclusion and get howls of laughter from medical audiences.

Regarding the Khan figures I think the figures for suicide are correct and the suicidal act figures are likely wrong – based on the widely accepted fact that Khan et al’s comparable figures for suicidal acts in their depression trial meta-analysis were demonstrably manipulated by companies to minimize the problem – a minimization that Dr Khan and colleagues could readily have noticed in their depression study, indeed could hardly have missed, but did not report.

According to the US NIMH, there are 11.3 suicide deaths per 100,000 people (.01%), or 33,900 US suicides per year. The rate of suicide has been substantially unchanged for 50 years, despite the widespread prescription of antidepressants in the last 20.

Medicating 10% or 11% of the population to (unsuccessfully) stamp out a suicide rate of .01% is, at best, a misapplication of resources. Given the dramatic adverse effects of the drugs, it is an endangerment of the public health.

[…] The regulator will refer you to the Department of Health, who will refer you to the licensing body for doctors, who will refer you to the professional body, who will refer you back to the regulator. We have all written to the regulator and the minister for health and we all get the stock letters back (Ed: See Margaret’s Story). […]